The present invention relates to novel substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepane derivatives (herein referred to as a compound or compounds of formula (1)) and their use as histamine receptor antagonists and tachykinin receptor antagonists. Such antagonists are useful in the treatment of asthma; bronchitis; inflammatory bowel diseases, including Crohn""s disease and ulcerative colitis; allergic rhinitis, including seasonal rhinitis and sinusitis; allergies; and emesis.
The compounds of the present invention are useful in their pharmacological activities, such as histamine receptor antagonism and tachykinin receptor antagonism. Antagonism of histamine responses can be elicited through blocking of histamine receptors. Antagonism of tachykinin responses can be elicited through blocking of tachykinin receptors. One object of the present invention is to provide new and useful antagonists of histamine. A further object of the present invention is to provide new and useful antagonists of tachykinins. A particular object of the present invention are those compounds that exhibit both histamine and tachykinin receptor antagonism.
The present invention provides novel substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepane derivatives of the formula: 
wherein
m is 2 or 3;
n is 0 or 1;
q is 1 or 2;
r is 0 or 1;
G1 is xe2x80x94CH2xe2x80x94 or xe2x80x94C(O)xe2x80x94;
G2 is xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94 or xe2x80x94C(O)xe2x80x94;
G3 is xe2x80x94CH2xe2x80x94 or xe2x80x94C(O)xe2x80x94;
Ar1 is a radical chosen from the group consisting of 
wherein
R1 is from 1 to 3 substituents each independently chosen from the group consisting of hydrogen, halogen, hydroxy, xe2x80x94CF3, C1-C6 alkyl, and C1-C6 alkoxy;
R2 is from 1 to 2 substituents each independently chosen from the group consisting of hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkoxy;
Ar2 is a radical selected from the group consisting of 
wherein
z is 1 or 2;
R20 is from 1 to 2 substituents each independently chosen from the group consisting of hydrogen, hydroxy, halogen, C1-C6 alkyl, and C1-C6 alkoxy;
R3is from 1 to 3 substituents each independently chosen from the group consisting of hydrogen, hydroxy, halogen, xe2x80x94OCF3, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94(CH2)dS(O)bR22, xe2x80x94(CH2)eCN, xe2x80x94O(CH2)cCO2R23, xe2x80x94NH2, xe2x80x94NHC(O)CH3, xe2x80x94NHSO2CH3 wherein c is an integer from 1 to 5; b is 0, 1, or 2; d is 0 or 1; e is 0 or 1; R22 is C1-C4 alkyl; and R23 is hydrogen or C1-C4 alkyl;
R21 is hydrogen or a radical chosen from the group consisting of 
wherein
f is 0 or 1;
R25is hydrogen or xe2x80x94CH3;
R24is selected from the group consisting of hydrogen, C1-C4 alkyl, xe2x80x94CF3, phenyl, S(O)xR26, and CH2N(CH3)2 wherein x is 0, 1, or 2; R26 is C1-C4 alkyl;
R4 is from 1 to 2 substituents each independently chosen from the group consisting of hydrogen, halogen, xe2x80x94CF3, C1-C6 alkyl, and C1-C6 alkoxy;
R5 is chosen from the group consisting of hydrogen, C1-C4 alkyl, xe2x80x94(CH2)wxe2x80x94Oxe2x80x94(CH2)tCO2R8, xe2x80x94(CH2)jCN, xe2x80x94(CH2)uCO2R6, xe2x80x94(CH2)uC(O)NR16R17, xe2x80x94(CH2)uC(O)CH3, xe2x80x94(CH2)pAr3, xe2x80x94(CH2)wxe2x80x94Oxe2x80x94R7, xe2x80x94CH2CHxe2x95x90CHCF3, xe2x80x94(CH2)2CHxe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CHCH3, xe2x80x94CH2CHxe2x95x90CHCH2CH3, xe2x80x94CH2CHxe2x95x90C(CH3)2, and xe2x80x94(CH2)gS(O)kR19,
wherein
w is an integer from 2 to 5;
t is an integer from 1 to 3;
j is an integer from 1 to 5;
u is an integer from 1 to 5;
p is an integer from 1 to 4;
g is 2 or 3;
k is 0, 1, or 2;
R8 is hydrogen or C1-C4 alkyl;
R6 is hydrogen or C1-C4 alkyl;
R16 is hydrogen or C1-C4 alkyl;
R17 is hydrogen or C1-C4 alkyl;
R19 is C1-C4 alkyl or a radical of the formula 
Ar3 is a radical chosen from the group consisting of 
wherein
R9 is from 1 to 3 substituents each independently chosen from the group consisting of hydrogen, halogen, xe2x80x94CF3, C1-C6 alkyl, C1-C6 alkoxy, and xe2x80x94CO2R13 wherein R13 is chosen from the group consisting of hydrogen and C1-C4 alkyl;
R10 is from 1 to 2 substituents each independently chosen from the group consisting of hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkoxy;
R11 is chosen from the group consisting of hydrogen, xe2x80x94CH3, and xe2x80x94CH2OH;
R12 is chosen from the group consisting of hydrogen, C1-C4 alkyl, and benzyl;
R18 is chosen from the group consisting of hydrogen, halogen, xe2x80x94CH3, and xe2x80x94CH2OH;
R7 is hydrogen, C1-C4 alkyl, xe2x80x94(CH2)yxe2x80x94CF3, xe2x80x94CH2CN or a radical chosen from the group consisting of 
wherein
v is an integer from 1 to 3;
y is an integer from 0 to 2;
R14 is chosen from the group consisting of hydrogen, halogen, C1-C4 alkyl, and. xe2x80x94CO2R15 wherein R15 is hydrogen or C1-C4 alkyl;
provided that when G1 is xe2x80x94C(O)xe2x80x94 then G2 is either xe2x80x94CH2xe2x80x94 or xe2x80x94CH(CH3)xe2x80x94 and G3 is xe2x80x94CH2xe2x80x94;
further provided that when G2 is xe2x80x94C(O)xe2x80x94 then G1 is xe2x80x94CH2xe2x80x94 and G3 is xe2x80x94CH2xe2x80x94;
still further provided that when G3 is xe2x80x94C(O)xe2x80x94 then G1 is xe2x80x94CH2xe2x80x94 and G2 is either xe2x80x94CH2xe2x80x94 or xe2x80x94CH(CH3)xe2x80x94;
or stereoisomers, or pharmaceutically acceptable salts thereof.
As is appreciated by one of ordinary skill in the art the compounds of the formula (1) may exist as stereoisomers depending on the nature of the substituents present. Any reference in this application to one of the compounds of the formula (1) is meant to encompass either specific stereoisomers or a mixture of stereoisomers. Where indicated, the compounds follow the designation of (+)- and (xe2x88x92)- or (R)- and (S)- or (E)- and (Z)- for the stereochemistry of compounds represented by formula (1). It is specifically recognized that in the substituted 3-aryl-3-((1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)alkyl)pyrrolidines, substituted 3-arylmethyl-3-((1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)alkyl)pyrrolidines, substituted 3-aryl-3-((1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)alkyl)piperidines, and substituted 3-arylmethyl-3-((1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)alkyl)piperidines; the 3-position of the pyrrolidine or piperidine is asymmetric, and may be in the (R)- or (S)-configuration, or may be a mixture thereof. It is specifically recognized that compounds of formula (1) in which G2 is xe2x80x94CH(CH3)xe2x80x94 are asymetric at the methyl bearing carbon and may be in the (R)- or (S)-configuration, or may be a mixture thereof. It is specifically recognized that compounds of formula (1) in which R5 is xe2x80x94CH2CHxe2x95x90CHCF3, xe2x80x94CH2CHxe2x95x90CHCH3, and xe2x80x94CH2CHxe2x95x90CHCH2CH3 may exist as stereoisomers and may be in the (E)- or (Z)-configuration, or may be a mixture thereof.
The specific stereoisomers can be prepared by stereospecific synthesis using enantiomerically or geometrically pure or enantiomerically or geometrically enriched starting materials. The specific stereoisomers of either starting materials or products can be resolved and recovered by techniques known in the art, such as chromatography on chiral stationary phases, enzymatic resolution, or fractional recrystallization of addition salts formed by reagents used for that purpose. Useful methods of resolving and recovering specific stereoisomers are know in the art and described in Stereochemistry of Organic Compounds, E. L. Eliel and S. H. Wilen, Wiley (1994) and Enantiomers, Racemates, and Resolutions, J. Jacques, A. Collet, and S. H. Wilen, Wiley (1981).
As is appreciated by one of ordinary skill in the art some of the compounds of the formula (1) may exist as tautomers. Any reference in this application to one of the tautomers of compounds of the formula (1) is meant to encompass every tautomeric form and mixtures thereof.
As used in this application:
a) the term xe2x80x9chalogenxe2x80x9d refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom;
b) the term xe2x80x9cC1-C6 alkylxe2x80x9d refers to a branched or straight chained alkyl radical containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, etc;
c) the term xe2x80x9cC1-C6 alkoxyxe2x80x9d refers to a straight or branched alkoxy group containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, pentoxy, hexoxy, cyclopentoxy, cyclohexoxy, etc;
d) the designations xe2x80x94C(O)xe2x80x94 or xe2x80x94(O)Cxe2x80x94 refer to a carbonyl group of the formula: 
e) the designation xe2x80x9cxe2x80x9d refers to a bond for which the stereochemistry is not designated;
f) as used in the examples and preparations, the following terms have the meanings indicated: xe2x80x9ckgxe2x80x9d refers to kilograms, xe2x80x9cgxe2x80x9d refers to grams, xe2x80x9cmgxe2x80x9d refers to milligrams, xe2x80x9cxcexcgxe2x80x9d refers to micrograms, xe2x80x9cmolxe2x80x9d refers to moles, xe2x80x9cmmolxe2x80x9d refers to millimoles, xe2x80x9cnmolexe2x80x9d refers to nanomoles, xe2x80x9cLxe2x80x9d refers to liters, xe2x80x9cmLxe2x80x9d or xe2x80x9cmlxe2x80x9d refers to milliliters, xe2x80x9cxcexcLxe2x80x9d refers to microliters, xe2x80x9cxc2x0 C.xe2x80x9d refers to degrees Celsius, xe2x80x9cRfxe2x80x9d refers to retention factor, xe2x80x9cmpxe2x80x9d refers to melting point, xe2x80x9cdecxe2x80x9d refers to decomposition, xe2x80x9cbpxe2x80x9d refers to boiling point, xe2x80x9cmm of Hgxe2x80x9d refers to pressure in millimeters of mercury, xe2x80x9ccmxe2x80x9d refers to centimeters, xe2x80x9cnmxe2x80x9d refers to nanometers, xe2x80x9c[xcex1]2D0xe2x80x9d refers to specific rotation of the D line of sodium at 20xc2x0 C. obtained in a 1 decimeter cell, xe2x80x9ccxe2x80x9d refers to concentration in g/mL, xe2x80x9cTHFxe2x80x9d refers to tetrahydrofuran, xe2x80x9cDMFxe2x80x9d refers to dimethylformamide, xe2x80x9cbrinexe2x80x9d refers to a saturated aqueous sodium chloride solution, xe2x80x9cMxe2x80x9d refers to molar, xe2x80x9cmMxe2x80x9d refers to millimolar, xe2x80x9cxcexcMxe2x80x9d refers to micromolar, xe2x80x9cnMxe2x80x9d refers to nanomolar, xe2x80x9cpsixe2x80x9d refers to pounds per square inch, xe2x80x9cTLCxe2x80x9d refers to thin layer chromatography, xe2x80x9cHPLCxe2x80x9d refers to high performance liquid chromatography, xe2x80x9cHRMSxe2x80x9d refers to high resolution mass spectrum, xe2x80x9clbxe2x80x9d refers to pounds, xe2x80x9cgalxe2x80x9d refers to gallons, xe2x80x9cL.O.D.xe2x80x9d refers to loss on drying, xe2x80x9cxcexcCixe2x80x9d refers to microcuries, xe2x80x9ci.p.xe2x80x9d refers to intraperitoneally, xe2x80x9ci.v.xe2x80x9d refers to intravenously, and xe2x80x9cDPMxe2x80x9d refers to disintegrations per minute;
g) the designation 
refers to a phenyl or a substituted phenyl and it is understood that the radical is attached at the 1-position and the substituent or substituents represented by R can be attached in any of the 2, 3, 4, 5, or 6 positions;
h) the designation 
refers to a pyridine, substituted pyridine, pyridyl or substituted pyridyl and it is understood that the radical can be attached at either the 2-position, the 3-position, or the 4-position, it is further understood that when the radical is attached at the 2-position the substituent or substituents represented by R can be attached in any of the 3, 4, 5, or 6 positions, that when the radical is attached at the 3-position the substituent or substituents represented by R can be attached in any of the 2, 4, 5, or 6 positions, and that when the radical is attached at the 4-position the substituent or substituents represented by R can be attached in any of the 2, 3, 5, or 6 positions;
i) the designation 
refers to a thiophene or thienyl and it is understood that the radical is attached at the 2 or 3-positions;
j) the designation 
refers to a naphthalene, substituted naphthalene, naphthyl or substituted naphthyl and it is understood that the radical can be attached at either the 1-position or the 2-position, it is further understood that when the radical is attached at the 1-position the substituent or substituents represented by R can be attached in any of the 2, 3, 4, 5, 6, 7, or 8 positions and that when the radical is attached at the 2-position the substituent or substituents represented by R can be attached in any of the 1, 3, 4, 5, 6, 7, or 8 positions:
k) the term xe2x80x9cenantiomeric excessxe2x80x9d or xe2x80x9ceexe2x80x9d refers to the percent by which one enantiomer, El , is in excess in a mixture of the two enantiomers, El plus E2, such that
{(E1xe2x88x92E2)÷(El+E2)}xc3x97100%=ee; 
l) the term xe2x80x9cC1-C4 alkylxe2x80x9d refers to a saturated straight or branched chain alkyl group containing from 1-4 carbon atoms and includes methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, and t-butyl;
m) the designations xe2x80x94CO2R and xe2x80x94C(O)OR refer to a group of the formula: 
n) the designation xe2x80x94C(O)NRR refer to a group of the formula: 
o) the designation 
refers to a furan or furyl and it is understood that the radical is attached at either the 2-position or 3-position;
p) the designation xe2x80x9cxe2x80x9d refers to a bond that protrudes forward out of the plane of the page;
q) the designation xe2x80x9cxe2x80x9d refers to a bond that protrudes backward out of the plane of the page;
r) the term xe2x80x9cpharmaceutically acceptable salts thereofxe2x80x9d refers to either an acid addition salt or a basic addition salt.
The expression xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds represented by formula (1) or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxybenzoic, p-toluenesulfonic acid, and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which in comparison to their free base forms, generally demonstrate higher melting points.
The expression xe2x80x9cpharmaceutically acceptable basic addition saltsxe2x80x9d is intended to apply to any non-toxic organic or inorganic basic addition salts of the compounds represented by formula (1) or any of its intermediates. Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline.
Preferred embodiments of formula (1) are given below:
1) Compounds wherein q is 1 are preferred;
2) Compounds wherein r is 0 are preferred;
3) Compounds wherein m is 2 are preferred;
4) Compounds wherein G1 is xe2x80x94CH2xe2x80x94 are preferred;
5) Compounds wherein G2 is xe2x80x94C(O)xe2x80x94 are preferred;
6) Compounds wherein R5 is xe2x80x94(CH2)wxe2x80x94Oxe2x80x94R7 are preferred;
7) Compounds wherein R5 is xe2x80x94(CH2)pAr3 are preferred.
It is understood that further preferred embodiments of formula (1) can be selected by requiring one or more of the preferred embodiments 1 through 7 of formula (1) or by reference to examples given herein.
Examples of compounds encompassed by the present invention include the following. It is understood that the examples encompass the specific stereoisomers and diastereomers, where applicable, of the compound and mixtures thereof. This list is meant to be representative only and is not intended to limit the scope of the invention in any way:
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3-chlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-methoxyphenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(4-oxopentyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol- 2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,5-Dimethoxy-4-hydroxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4-Dimethoxy-5-hydroxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-(4-Carboxypropyl)-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methylthio-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazeparn-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3-(1H-Tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(5-methylsulfonyltetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(5-trifluormethyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine
1-(2-Methoxy-5-(5-N,N-dimethylaminomethyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methyl-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(4H-triazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(3,5-dimethyl-4H-triazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-methylthiobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine
1-(3-Methoxy-4,5-methylenedioxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3-Methoxy-4,5-ethylenedioxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(4-cyanobutyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(4-(1H-tetrazol-5-yl)butyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-trifluormethylbenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-methylsulfonamidobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(-Methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(methylthiomethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(cyanomethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-ylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-triazol-1-ylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-fluorobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-acetamidobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1l,4]diazepan-1-yl)ethyl)-3-(phenylmethyl)-2-oxopyrrolidine;
1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine;
1-(-Methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlororphenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2-propyloxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2-propyloxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-oxobutyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3 -(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3 -phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-methylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-methylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl) [1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimidazol-2-yl) [1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimidazol-2 -yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimnidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl) [1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl) [1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(fur-2 -ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl) [1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl) [1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-3,4dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl) [1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-3-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-3-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-4-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-4-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-methylfur-3-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-methylfur-3-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-3-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-3-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(thien-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(thien-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(thien-3-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(thien-3-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-methy-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-methy-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-ethyl-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-ethyl-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(2-Methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1(2-(trifluoromnethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-Benzoyl-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl) [1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-Benzoyl-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;
1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine.
The compounds of formula (1) may be synthesized by use of the following synthetic procedures to produce intermediates or final compounds of the invention:
Reaction Scheme A.1 relates to the synthesis of compounds of formula (1) by alkylation of intermediates derived from alcohols of structure 2.
Reaction Scheme A.2 relates to the synthesis of compounds of formula (1) by reductive amination of aldehydes derived from alcohols of structure 2.
Reaction Scheme A.3 relates to the synthesis of compounds of formula (1) by aroylation or alkylation of intermediates derived from alcohols of structure 40.
Reaction Scheme B relates to the synthesis of alcohols of structure 2 in which G3 is xe2x80x94CH2xe2x80x94 used as a starting material in Reaction Schemes A.1 and A.2 and intermediates of structure 11 used to prepare alcohols of structure 40 in Reaction Scheme A.3.
Reaction Scheme C relates to a synthesis of alcohols of structure 2 in which m is 2, q is 1, r is 0, and G3 is xe2x80x94CH2xe2x80x94 and relates to the synthesis of intermediates of structure 8 used to prepare alcohols of structure 2 in Reaction Scheme B and intermediates of structure 18 used to prepare alcohols of structure 40 in Reaction Scheme A.3.
Reaction Scheme D relates to a synthesis of alcohols of structure 2 in which r is 1 and G1 is xe2x80x94CH2xe2x80x94 used as a starting material in Reaction Scheme A.1 and A.2 and intermediates of structure 26 used to prepare alcohols of structure 40 in Reaction Scheme A.3.
Reaction Scheme E relates to a synthesis of alcohols of structure 2 in which r is 0 and G1 is xe2x80x94CH2xe2x80x94 used as a starting material in Reaction Scheme A.1 and A.2 and intermediates of structure 35 used to prepare alcohols of structure 40 in Reaction Scheme A.3.
A general synthetic procedure for preparing these compounds of formula (1) is set forth in Reaction Scheme A.1. The reagents and starting materials are readily available to one of ordinary skill in the art. In Reaction Scheme A.1, all substituents, unless otherwise indicated, are as previously defined. 
In Reaction Scheme A.1, step 1, the hydroxy group of an appropriate alcohol of structure 2 is converted to an appropriate leaving group to give a compound of structure 2a.
An appropriate alcohol of structure 2 is one in which the stereochemistry is as desired in the final product of formula (1) and m, n, q, r, G1, G2, G3, Ar1 and Ar2 are as desired in the final product of formula (1). Alternately, an appropriate alcohol of structure 2 can be one in which the stereochemistry gives rise after resolution to stereochemistry as desired in the final product of formula (1) and m, n, q, r, G1, G2, G3, Ar1 and Ar2 are as desired in the final product of formula (1). An appropriate alcohol of structure 2 can also be one in which the stereochemistry is as desired in the final product of formula (1); and m, n, q, r, G1, G2, and G3 are as desired in the final product of formula (1); and Ar1 and/or Ar2 gives rise upon deprotection to Ar1 and/or Ar2 as desired in the final product of formula (1). Alternately, an appropriate alcohol of structure 2 can also be one in which the stereochemistry gives rise after resolution to stereochemistry as desired in the final product of formula (1); and m, n, q, r, G1, G2, and G3 are as desired in the final product of formula (1); and Ar1 and/or Ar2 gives rise upon deprotection to Ar1 and/or Ar2 as desired in the final product of formula (1). Appropriate alcohols of structure 2 can be prepared as described herein and in International Patent Application (PCT) No. WO 94/26735, published Nov. 24, 1994.
An appropriate leaving group, L1, is one which can be displaced by a 4-(1H-benzimidazol-2-yl)[1,4]diazepane of structure 3 to give rise to a compound of formula (1). Appropriate leaving groups, L1, include but are not limited to chloro, bromo, iodo, mesylate, tosylate, benzenesulfonate, trifluoromethanesulfonate, and the like. The conversion of hydroxy groups to leaving groups such as chloro, bromo, iodo, mesylate, tosylate, benzenesulfonate, and trifluoromethanesulfonate is well known and appreciated in the art.
For example, compounds in which L1 is bromo are formed by contacting an appropriate alcohol of structure 2 with 1.0 to 1.5 molar equivalents of carbon tetrabromide and 1.0 to 1.75 molar equivalents triphenylphosphine. (P. J. Kocienski et al. J. Org. Chem. 42, 353-355 (1977)). The reaction is carried out by combining the alcohol of structure 2 with carbon tetrabromide in a suitable solvent, such as dichloromethane or chloroform and then adding a solution of triphenylphosphine in a suitable solvent, such as dichloromethane or chloroform. Generally the reaction is carried out at temperatures of from xe2x88x9210xc2x0 C. to ambient temperature. Generally, the reactions require from 5 minutes to 24 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallizationa.
Compounds in which L1 is bromo are also formed by contacting an appropriate alcohol of structure 2 with a slight molar excess of triphenylphosphine dibromide. (R. F Borch et al. J. Am. Chem. Soc. 99, 1612-1619 (1977)). The reaction may be carried out by contacting an appropriate alcohol of structure 2 with preformed triphenylphosphine dibromide. The reaction is carried out in a suitable solvent, such as tetrahydrofuran and diethyl ether. The reaction is carried out in the presence of a suitable base, such as pyridine. Generally the reaction is carried out at temperatures of from 0xc2x0 C. to 50xc2x0 C. Generally, the reactions require from 5 minutes to 24 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
Alternately, for example, compounds in which L1 is mesylate are formed by contacting an appropriate alcohol of structure 2 with a molar excess of methanesulfonyl chloride. The reaction is carried out in a suitable solvent, such as acetonitrile, dichloromethane, chloroform, toluene, benzene, or pyridine. The reaction is carried out in the presence of a suitable base, such as triethylamine, diisopropylethylamine, or pyridine. Generally the reaction is carried out at temperatures of from xe2x88x9220xc2x0 C. to 50xc2x0 C. Generally, the reactions require from 1 hour to 24 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
Compounds of structure 2a in which L1 is iodo can be prepared from compounds of structure 2a in which L1 is mesylate, chloro, or bromo by an exchange reaction, such as the Finkelstein reaction.
For example, a compound of structure 2a in which L1 is mesylate, chloro, or bromo is contacted with from 1.0 to 10.0 molar equivalents of an iodide salt, such as sodium iodide or potassium iodide. The reaction is carried out in a suitable solvent, such as acetone, butanone, tetrahydrofuran, tetrahydrofuran/water mixtures, toluene, and acetonitrile. Generally, the reaction is carried out at temperatures of from ambient temperature to the refluxing temperature of the solvent. Generally, the reactions require from 1 hour to 24 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Reaction Scheme A.1, step 2, the compound of structure 2a reacts with an appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane compound of structure 3 or a salt thereof to give a protected compound of formula (1) or a compound of formula (1).
An appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane of structure 3 or salt thereof is one in which R4 and R5 are as desired in the final product of formula (1) or R5 gives rise after deprotection and/or modification to R5 as desired in the final product of formula (1). Appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepanes of structure 3 are well known and appreciated in the art. Appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepanes of structure 3 may be prepared by methods known in the art such as described in J. Med Chem. 29, 1178-1183 (1986), Chem. Pharm. Bull., 37 962-966 (1989), and Tet. Lets., 38, 5607-5610 (1997); and by methods analogous to those methods and to those described herein by carrying out suitable deprotections, protections, and alkylations, and modifications, such as the reduction of esters, as are well known in the art, in the order and number required for formation of an appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane of structure 3.
For example, the compound of structure 2a is contacted with an appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane compound of structure 3 or salt thereof to give a protected compound of formula (1) or a compound of formula (1). The reaction is carried out in a suitable solvent, such as dioxane, tetrahydrofuran, tetrahydrofuran/water mixtures, acetone, acetone/water mixtures, ethyl acetate, ethyl acetate/water mixtures, pyridine, acetonitrile, toluene, toluene/water mixtures, chlorobenzene, or dimethylformamide, with acetonitrile being preferred. The reaction is carried out in the presence of from 1.0 to 6.0 molar equivalents of a suitable base, such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, pyridine, or diisopropylethylamine, with diisopropylethylamine being preferred. When a salt of an appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane of structure 3 is used, a molar excess of a suitable base may be required to absorb the acid liberated from the salt. The reaction may be facilitated by the addition of a catalytic amount, 0.1 to 0.5 molar equivalents, of an iodide salt, such as sodium iodide, potassium iodide, or tetrabutyl ammonium iodide. The reaction is generally carried out at temperatures of from ambient temperature to the refluxing temperature of the solvent. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Reaction Scheme A.1, optional step 3, a compound of formula (1) or a protected compound of formula (1) in which R5 is hydrogen is modified to give a compound of formula (1) or a protected compound of formula (1) in which R5 is not hydrogen. Also encompassed by Reaction Scheme A.1, optional step 3, a protected compound of formula (1) is deprotected to give a compound of formula (1).
A modification reaction, encompasses the formation of amides and the alkylation of the benzimidazole nitrogen. The formation of amides from esters and acids is well known and appreciated in the art. The alkylation of a benzimidazole nitrogen using a suitable alkylating agent is well known and appreciated in the art. An alkylation of a benzimidazole nitrogen encompasses the Michael addition using xcex1,xcex2-unsaturated electrophiles. A suitable alkylating agent is one which transfers a group R5 as desired in the final product of formula (1) or a protected group R5 which gives rise after deprotection to R5 as desired in the final product of formula (1).
For example, a compound of formula (1) in which R5 is hydrogen is contacted with a suitable alkylating agent. A suitable alkylating agent is one which transfers a group R5 as is desired in the final product of formula (1). Suitable alkylating agent include but are not limited to 4-fluorobenzyl bromide, 4-fluorobenzyl chloride, 2-(chloromethyl)furan, 3-(chloromethyl)furan, 2-(bromomethyl)thiophene, 3-(chloromethyl)thiophene, 2-(chloromethyl)pyridine, 3-(chloromethyl)pyridine, 4-(chloromethyl)pyridine, 2-chlorethyl ethyl ether, 2-chloroethyl methyl ether, benzyl chloride, 4-methoxybenzyl chloride, 5-(ethoxycarbonyl)-2-(chloromethyl)furan, ethyl chloroacetate, t-butyl bromoacetate, methyl bromoacetate, methyl iodide, ethyl iodide, propyl iodide, isopropyl iodide, butyl bromide, 2-isopropyloxyethyl chloride, 2-phenoxyethyl chloride, 2-(4-fluorophenoxy)ethyl bromide, 3-(4-fluorophenoxy)propyl bromide, methyl 2-(chloromethyl) benzoate, methyl 3-(chloromethyl)benzoate, methyl 4-(chloromethyl)benzoate, ethyl 2-(chloromethyl)benzoate, propyl 2-(chloromethyl)benzoate, N,N-dimethyl-4-(chloromethyl)benzamide, iodoacetamide, allyl chloride, allyl bromide, (E)-1-chlorobut-2-ene, (Z)-1-chlorobut-2-ene, 1-chloro-3-methylbut-2-ene, 2-(2,2,2-trifluoroethoxy)ethyl chloride, 2-trifluoromethoxyethyl chloride, 1-chloro-4,4,4-trifluorobut-2-ene, (E)-1-chloropent-2-ene, (Z)-1-chloropent-2-ene, acrylonitrile, methyl acrylate, t-butyl acrylate, methyl vinyl sulfone, ethyl vinyl sulfone, phenyl vinyl sulfone, and the like. The reaction is carried out in a suitable solvent, such as dioxane, tetrahydrofuran, tetrahydrofuran/water mixtures, acetone, or acetonitrile. The reaction is carried out in the presence of from 1.0 to 6.0 molar equivalents of a suitable base, such as sodium hydride, potassium hydride, sec-butyllithium, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, or diisopropylethylamine; with potassium hydride being preferred when the alkylating agent is an alkyl halide and sec-butyllithium being preferred when the alkylating agent is an Micheal accepter. The reaction is generally carried out at temperatures of from xe2x88x9278xc2x0 C. to the refluxing temperature of the solvent. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
A deprotection reaction, such as the removal of hydroxy protecting groups or hydrolysis of an ester, utilizing suitable protecting groups such as those described in Protecting Groups in Organic Synthesis by T. Greene is well known and appreciated in the art.
A general synthetic procedure for preparing the compounds of formula (1) by reductive amination is set forth in Reaction Scheme A.2. The reagents and starting materials are readily available to one of ordinary skill in the art. In Scheme A.2, all substituents, unless otherwise indicated, are as previously defined. For the preparation of compounds of formula (1) in which Ar1 is pyrid-2-yl the reductive amination as set forth in Reaction Scheme A.2 is preferred. 
In Reaction Scheme A.2, step 1, an appropriate alcohol of structure 2 is oxidized to an aldehyde of structure 2b by the method of Swern. (A. J. Mancuso et al., J. Org. Chem., 43 2480-2482 (1978), C. M. Amon, J. Org. Chem., 52, 4851-4855 (1987), and T. T. Tidwell, Synthesis, 857-870 (1990). An appropriate alcohol of structure 2 is as described in Reaction Scheme A.1, step 1.
For example, about two molar equivalents of dimethyl sulfoxide are added dropwise to a solution of oxalyl chloride, pyridine sulfur trioxide complex, or trifluoroacetic anhydride in dichloromethane, at approximately xe2x88x9260xc2x0 C. After the addition is complete, the reaction is stirred for approximately two minutes. A molar equivalent of the alcohol of structure 2 either neat or as a solution in dichloromethane is added. After the addition is complete the reaction mixture is stirred for 5 to 45 minutes, then about 3 to 5 molar equivalents of triethylamine is added. The reaction mixture is allowed to stir with warming to ambient temperature over 30 minutes to 2 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography, and recrystallization.
In Reaction Scheme A.2, step 2, the compound of structure 2b is contacted with an appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane of structure 3 or salt thereof in a reductive amination to give a protected compound of formula (1) or a compound of formula (1). An appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane of structure 3 or salt thereof is as defined in Reaction Scheme A-1.
For example, the compound of structure 2b is contacted with an appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane compound of structure 3 or salt thereof. The reaction is carried out using a molar excess of a suitable reducing agent such as sodium borohydride or sodium cyanoborohydride with sodium cyanoborohydride being preferred. Reductive aminations using secondary amines and aldehydes are well known and appreciated in the art. The reaction is carried out in a suitable solvent, such as ethanol, methanol, dichloromethane, or dimethylformamide. Generally, the reaction is carried out at temperatures of from 0xc2x0 C. to 50xc2x0 C. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography, and recrystallization.
In Reaction Scheme A.2, optional step 3, a compound of formula (1) or a protected compound of formula (1) in which R5 is hydrogen is modified to give a a compound of formula (1) or a protected compound of formula (1) in which R5 is not hydrogen and/or a protected compound of formula (1) is deprotected to give a compound of formula (1) as described in Reaction Scheme A.1, optional step 3.
A general synthetic procedure for preparing the compounds of formula (1) in which G1 and G3 are xe2x80x94CH2xe2x80x94 is set forth in Reaction Scheme A.3. The reagents and starting materials are readily available to one of ordinary skill in the art. In Scheme A.3, all substituents, unless otherwise indicated, are as previously defined. 
In Reaction Scheme A.3, step 1, the hydroxy group of an appropriate alcohol of structure 40 is converted to an appropriate leaving group, as described in Reaction Scheme A.1, step 1, to give a compound of structure 40a.
In Reaction Scheme A.3, step 1, an appropriate alcohol of structure 40 is one in which the stereochemistry is as desired in the final product of formula (1) and m, q, r, and Ar1 are as desired in the final product of formula (1) and G1 and G3 are xe2x80x94CH2xe2x80x94. Alternately, an appropriate alcohol of structure 40 can be one in which the stereochemistry gives rise after resolution to stereochemistry as desired in the final product of formula (l) and m, q, r, and Ar1 are as desired in the final product of formula (1) and G1 and G3 are xe2x80x94CH2xe2x80x94. An appropriate alcohol of structure 40 can also be one in which the stereochemistry is as desired in the final product of formula (1); and m, q, and r are as desired in the final product of formula (1) and G1 and G3 are xe2x80x94CH2xe2x80x94; and Ar1 gives rise upon deprotection to Ar1 as desired in the final product of formula (1). Alternately, an appropriate alcohol of structure 40 can also be one in which the stereochemistry gives rise after resolution to stereochemistry as desired in the final product of formula (1); and m, q, and r are as desired in the final product of formula (1) and G1 and G3 are xe2x80x94CH2xe2x80x94; and Ar1 gives rise upon deprotection to Ar1 as desired in the final product of formula (1).
An appropriate alcohol of structure 40 can be prepared by protecting the pyrrolidine or piperidine nitrogen of compounds of structure 11 (Reaction Scheme B), compounds of structure 26 (Reaction Scheme D), and compounds of structure 35 (Reaction Scheme E); in which the hydroxy protecting group has been removed; and compounds of structure 18 (Reaction Scheme C). The selection and use of a suitable amine protecting group, Pg3, such as those described in Protecting Groups in Organic Synthesis by T. Greene are well known and appreciated in the art. In Reaction Scheme A.3 the use of benzamide and carbamate protecting groups, such as benzoyl, t-butoxycarbonyl and ethoxycarbonyl, is preferred. Reaction Scheme A.3 the use of benzamide protecting groups, such as benzoyl is more preferred.
In Reaction Scheme A.3, step 2, the compound of structure 40a reacts with an appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane compound of structure 3 or a salt thereof, as described in Reaction Scheme A.1, step 2, to give a protected compound of structure 41. An appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepanes of structure 3 is one as described in Reaction Scheme A.1
In Reaction Scheme A.3, step 3, a protected compound of formula 41 is deprotected to give a compound of structure 42. Deprotection reactions, such as the removal of amine protecting groups such as those described in Protecting Groups in Organic Synthesis by T. Greene are well known and appreciated in the art.
In Reaction Scheme A.3, step 4, a compound of structure 42 is aroylated or alkylated to give a compound of formula (1) or a protected compound of formula (1) in which G1 and G3 are xe2x80x94CH2xe2x80x94. An aroylation is carried out as described in Reaction Scheme B, optional step 7, above. An alkylation reaction is carried out as described in Reaction Scheme B, optional step 8, above, and can be carried out by reductive amination, such as described n Reaction Scheme A.2, step 2. Aroylations and alkylations of amines are well known and appreciated in the art.
In Reaction Scheme A.3, optional step 5, a compound of formula (1) or a protected compound of formula (1) in which R5 is hydrogen can be modified to give a compound of formula (1) or a protected compound of formula (1) in which R5 is not hydrogen and/or a protected compound of formula (1) is deprotected to give a compound of formula (1), as described in Reaction Scheme A.1, optional step 3.
Reaction Scheme B is a general scheme for preparing alcohols of structure 2 in which G3 is xe2x80x94CH2xe2x80x94 used as a starting material in Reaction Schemes A.1 and A.2 and for preparing amine of structure 11 used as starting material in Reaction Scheme A.3. The reagents and starting materials are readily available to one of ordinary skill in the art. In Reaction Scheme B, all substituents, unless otherwise indicated, are as previously defined. 
In Reaction Scheme B, step 1, an appropriate nitrile of structure 5 is alkylated with an appropriate protected alcohol of structure 4 to give an xcfx89-protected-hydroxyalkyl-nitrile of structure 6.
An appropriate nitrile of structure 5 is one in which r and Ar1 are as desired in the final product of formula (1) or Ar1 gives rise after deprotection to an Ar1 as desired in the final product of formula (1). An appropriate protected alcohol of structure 4 is one in which m is as desired in the final product of formula (1) and the leaving group, L2, is one which can be displaced by an anion derived from an appropriate nitrile of structure 5. Suitable leaving groups include but are not limited to chloro, bromo, iodo, and mesylate with iodo and bromo being preferred. The selection and use of a suitable hydroxy protecting group, Pg1, such as those described in Protecting Groups in Organic Synthesis by T. Greene are well known and appreciated in the art. The use of tetrahyropyran-2-yl and t-butyldimethylsilyl are generally preferred.
For example, the appropriate nitrile of structure 5 is contacted with 1.0 to 1.2 molar equivalents of the appropriate protected alcohol of structure 4. The reaction is carried out in the presence of an equimolar amount of a suitable base, such as sodium hydride, sodium bis-(trimethylsilyl)amide, potassium t-butoxide, and lithium diisopropylamide with sodium hydride and sodium bis-(trimethylsilyl)amide being preferred. The reaction is carried out in a solvent, such as dimethylformamide or tetrahydrofuran. The reaction is generally carried out at temperatures of from xe2x88x9278xc2x0 C. to 0xc2x0 C. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Reaction Scheme B, step 2, the xcfx89-protected-hydroxyalkyl-nitrile of structure 6 is alkylated with ethyl bromoacetate or ethyl 3-bromopropionate to give a nitrile ester compound of structure 7.
For example, the xcfx89-protected-hydroxyalkyl-nitrile of structure 6 is contacted with approximately a molar equivalent of ethyl bromqacetate or ethyl bromopropionate. The reaction is carried out in the presence of approximately a molar equivalent of a suitable base, such as sodium bis-(trimethylsilyl)amide or lithium diisopropylamide. The reaction is carried out in a suitable solvent, such as tetrahydrofuran. The reaction is generally carried out at temperatures of from xe2x88x9278xc2x0 C. to 0xc2x0 C. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Reaction Scheme B, step 3, the nitrile ester compound of structure 7 is reduced and cyclized to give an oxo-3-(-protected-hydroxyalkyl) compound of structure 8. The cyclization may occur spontaneously after the reduction or may be carried out in a separate step after the isolation of the intermediate amine.
For example, the nitrile ester compound of structure 7 is contacted with an excess of an appropriate reducing agent, such as sodium borohydride in the presence of cobalt (II) chloride hexahydrate or hydrogen in the presence of a suitable catalyst, such as Raney nickel or platinum oxide. For compounds of structure 7 in which Ar1 is thienyl, sodium borohydride in the presence of cobalt (II) chloride hexahydrate is preferred.
When sodium borohydride in the presence of cobalt chloride is used, the reaction is carried out in a suitable solvent, such as methanol, or ethanol. The reaction is generally carried out at temperatures of from 0xc2x0 C. to 50xc2x0 C. Generally, the reactions require 1 to 72 hours. Generally, the cyclization occurs spontaneously under these conditions. The product can be isolated and purified by techniques well known in the art, such as extraction with aqueous acid, evaporation, trituration, chromatography, and recrystallization.
When Raney nickel is used, the reaction is carried out in a suitable solvent containing ammonia, such as ethanol/aqueous ammonium hydroxide or methanol/aqueous ammonium hydroxide. The reaction is generally carried out at temperatures of from ambient temperature to 70xc2x0 C. The reaction is carried out with hydrogen at pressures of from 15 psi to 120 psi in an apparatus designed for carrying out reactions under pressure, such as a Parr hydrogenation apparatus. Generally, the cyclization occurs spontaneously under these conditions. The product can be isolated by carefully removing the catalyst by filtration and evaporation. The product can be purified by extraction, evaporation, trituration, chromatography, and recrystallization.
When platinum oxide is used, the reaction is carried out in a suitable solvent such as ethanol, methanol, chloroform, ethanol/chloroform mixtures, or methanol/chloroform mixtures. The reaction is generally carried out at temperatures of from ambient temperature to 50xc2x0 C. The reaction is carried out with hydrogen at pressures of from 15 psi to 120 psi in an apparatus designed for carrying out reactions under pressure, such as a Parr hydrogenation apparatus. Generally, an amine intermediate is obtained under these conditions and is isolated by carefully removing the catalyst by filtration and evaporation. The amine intermediate is cyclized by heating in a suitable solvent, such as ethanol, methanol, toluene, or chlorobenzene. The reaction is generally carried out at temperatures of from 50xc2x0 C. to the refluxing temperature of the solvent. Generally, the reaction requires 8 to 48 hours. The product can be purified by extraction, evaporation, trituration, chromatography, and recrystallization.
In Reaction Scheme B, optional step 4, the oxo-3-(-protected-hydroxyalkyl) compound of structure 8 is alkylated with an appropriate alkylating agent, Xxe2x80x94CH2xe2x80x94(CH2)nxe2x80x94Ar2, to an 1-arylaklyl-oxo compound of structure 9. An appropriate alkylating agent, Xxe2x80x94CH2xe2x80x94(CH2)nxe2x80x94Ar2, is one in which X is methanesulfonyl, chloro, bromo, or iodo; n is as desired in the final product of formula (1), and Ar2 is as desired in formula (1) or gives rise after deprotection to Ar2 as desired in formula (1).
For example, the oxo-3-(xcfx89-protected-hydroxyalkyl) compound of structure 8 is contacted with from 1 to 5 molar equivalents of an appropriate alkylating agent, Xxe2x80x94CH2xe2x80x94(CH2)nxe2x80x94Ar2. The reaction is carried out in a suitable solvent, such as tetrahydrofuran, dimethyl sulfoxide, or dimethylformamide. The reaction is carried out in the presence of a base, such as sodium hydride, potassium t-butoxide, potassium bis(trimethylsilyl)amide, or lithium diisopropylamide with sodium hydride and potassium bis(trimethylsilyl)amide being preferred. The reaction is generally carried out at temperatures of from 0xc2x0 C. to 50xc2x0 C. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Reaction Scheme B, step 6, the 1-aryLalkyl-oxo-3-(xcfx89-protected-hydroxyalkyl) compound of structure 9 is deprotected to give an alcohol of structure 2 in which G1 is xe2x80x94C(O)xe2x80x94. A deprotection reaction, such as the removal of hydroxy protecting groups utilizing suitable protecting groups such as those described in Protecting Groups in Organic Synthesis by T. Greene is well known and appreciated in the art.
In Reaction Scheme B, optional step 5, the oxo-3-(xcfx89-protected-hydroxyalkyl) compound of structure 8 is reduced to give a 3-(xcfx89-protected-hydroxyalkyl) compound of structure 11.
For example, the oxo-3-(xcfx89-protected-hydroxyalkyl) compound of structure 8 is contacted with an excess of a suitable reducing agent, such as lithium aluminum hydride, aluminum hydride, or borane dimethyl sulfide complex. The reaction is carried out in a suitable solvent, such as tetrahydrofuran, diethyl ether, tetrahydrofuran/diethyl ether mixtures, or tetrahydrofuran/methyl t-butyl ether mixtures. The reaction is generally carried out at temperatures of from 0xc2x0 C. to the refluxing temperature of the solvent. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as quenching of borane or aluminum complexes, extraction, evaporation, trituration, chromatography, and recrystallization.
In Reaction Scheme B, optional step 7, the 3-(xcfx89-protected-hydroxyalkyl) compound of structure 11 is aroylated with an appropriate aryl acid, aryl ester, aryl halide, aryl anhydride, or aryl mixed anhydride, Axe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Ar2, to give an 1-aryl-3-(xcfx89-protected-hydroxyalkyl) compound of structure 12. An appropriate aryl acid, aryl ester, aroyl halide, aryl anhydride, or aryl mixed anhydride, Axe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Ar2, is one in which A is hydroxyl; an activated ester, such as O-hydroxysuccinimide, O-hydroxybenztriazole; an activated leaving group, such as chloro, bromo; or a group which forms an anhydride; or mixed anhydride, n is as desired in the final product of formula (1), and Ar2 is as desired in formula (1) or give rise after deprotection to Ar2 as desired in formula (1).
For example, the 3-(xcfx89-protected-hydroxyalkyl) compound of structure 11 is contacted with 1 to 1.5 molar equivalents of an appropriate aryl acid, aryl ester, aryl halide, aroyl anhydride, or aryl mixed anhydride, Axe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Ar2. The reaction is carried out in a suitable solvent, such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide, or pyridine. The reaction is carried out in the presence of a base, such as sodium carbonate, sodium bicarbonate, triethylamine, N-methylmorpholine, diisopropylethylamine, or pyridine. The reaction is generally carried out at temperatures of from xe2x88x9220xc2x0 C. to 50xc2x0 C. Generally, the reactions require 1 to 6 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Reaction Scheme B, optional step 8, the 3-(xcfx89-protected-hydroxyalkyl) compound of structure 11 is alkylated with an appropriate alkyl halide, X3xe2x80x94CH2xe2x80x94(CH2)nxe2x80x94Ar2, to give an 1-arylalkyl-3-(xcfx89-protected-hydroxyalkyl) compound of structure 13. An appropriate alkyl halide, X3xe2x80x94CH2xe2x80x94(CH2)nxe2x80x94Ar2, is one in which X3 is chloro or bromo, n is as desired in the final product of formula (1), and Ar2 is as desired in formula (1) or gives rise after deprotection to Ar2 as desired in formula (1).
For example, the 3-(xcfx89-protected-hydroxyalkyl) compound of structure 11 is contacted with from 1.0 to 1.2 molar equivalents of an appropriate alkyl halide, X3xe2x80x94CH2xe2x80x94(CH2)nxe2x80x94Ar2. The reaction is carried out in a suitable solvent, such as tetrahydrofuran, dimethyl sulfoxide, acetonitrile, tetrahydrofuran/water, toluene, toluene/water, or dimethylformamide. The reaction is carried out in the presence of a base, such as sodium carbonate, sodium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine, or pyridine. The reaction is generally carried out at temperatures of from 0xc2x0 C. to reflux temperature of the solvent. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Reaction Scheme B, step 9, the 1-arylaklyl-3-(xcfx89-protected-hydroxyalkyl) compound of structure 13 is deprotected to give an alcohol of structure 2 in which G1, G2, and G3 are xe2x80x94CH2xe2x80x94. A deprotection reaction, such as the removal of hydroxy protecting groups utilizing suitable protecting groups such as those described in Protecting Groups in Organic Synthesis by T. Greene is well known and appreciated in the art.
In Reaction Scheme B, step 10, the 1-aryl-3-(xcfx89-protected-hydroxyalkyl) compound of structure 12 is deprotected to give an an alcohol of structure 2 in which G1 is xe2x80x94CH2xe2x80x94, G2 is xe2x80x94C(O)xe2x80x94, and G3 is xe2x80x94CH2xe2x80x94.
Reaction Scheme C is a general scheme for preparing intermediates of structure 8 in which m is 2, r is 0, and q is 1 used in Reaction Scheme B to prepare alcohols of structure 2; and for preparing alcohols of structure 2 in which q is 1, r is 0, m is 2, and G3 is xe2x80x94CH2xe2x80x94 used as a starting material in Reaction Schemes A.1 and A.2 and for preparing intermediates of structure 18 used as starting material in Reaction Scheme A.3. The reagents and starting materials are readily available to one of ordinary skill in the art. In Reaction Scheme C, all substituents, unless otherwise indicated, are as previously defined. 
In Reaction Scheme C, step 1, an appropriate aryl-acetonitrile of structure 5a is bis-alkylated with ethyl bromoacetate to give a nitrile bis-ester compound of structure 14. An appropriate aryl-acetonitrile of structure 5a is one in which Ar1 is as desired in the final product of formula (1) or gives rise after deprotection to an Ar1 as desired in the final product of formula (1).
For example, an appropriate aryl-acetonitrile of structure 5a is contacted with 2.0 to 3.0 molar eauivalents of ethyl bromoacetate. The reaction is carried out in the presence of approximately 2.0 to 3.0 molar equivalents of a suitable base, such as sodium bis(trimethylsilyl)amide or lithium diisopropylamide. The reaction is carried out in a suitable solvent, such as tetrahydrofuran. The reaction is generally carried out at temperatures of from xe2x88x9278xc2x0 C. to 0xc2x0 C. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, distillation, chromatography, and recrystallization.
In Reaction Scheme C, step 2, the nitrile bis-ester compound of structure 14 is reduced and cyclized to give a 5-oxo-3-acetic acid ester pyrrolidine of structure 15.
For example, the nitrile bis-ester compound of structure 14 is contacted with a suitable reducing agent, such as sodium borohydride in the presence of cobalt II chloride hexahydrate or hydrogen in the presence of a suitable catalyst, such as Raney nickel or platinum oxide as taught in Reaction Scheme B, step 3. For compounds of structure 14 in which Ar1 is thienyl, sodium borohydride in the presence of cobalt II chloride hexahydrate is preferred.
In Reaction Scheme C, optional step 3, the 5-oxo-3-acetic acid ester pyrrolidine of structure 15 is hydrolyzed to give a 5-oxo-3-acetic acid pyrrolidixie of structure 16.
For example, the 5-oxo-3-acetic acid ester pyrrolidine of structure 15 is contacted with a suitable hydrolyzing agent, such as sodium hydroxide, potassium hydroxide, or lithium hydroxide. The reaction is carried out in a suitable solvent such as water, tetrahydrofuran/water mixtures, methanol, methanol/water mixtures, or ethanol/water mixtures. The reaction is generally carried out at temperatures of from 0xc2x0 C. to the refluxing temperature of the solvent. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Reaction Scheme C, step 4, the 5-oxo-3-acetic acid pyrrolidine of structure 16 is reduced to give a 5-oxo-3-(2-hydroxyethyl)pyrrolidine of structure 17.
For example, the 5-oxo-3-acetic acid pyrrolidine of structure 16 is contacted with a suitable borane reagent, such as borane dimethyl sulfide complex. The reaction is carried out in a suitable solvent, such as tetrahydrofuran. The reaction is generally carried out at a temperature of from 0xc2x0 C. to the refluxing temperature of the solvent. When complete, the reaction is quenched by the careful addition of a suitable aqueous acid solution, such as 1 M hydrochloric acid solution. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
Alternately, the 5-oxo-3-acetic acid pyrrolidine of structure 16 can be reduced by formation of a mixed anhydride intermediate and contacting the mixed anhydride intermediate with a suitable mild reducing agent, such as sodium borohydride.
For example, the 5-oxo-3-acetic acid pyrrolidine of structure 16 is contacted with 1.2 to 1.7 equivalents of a suitable base, such as N-methylmorpholine, in a suitable solvent, such as tetrahydrofuran or diethyl ether. The reaction mixture is cooled to a temperature of between xe2x88x9250xc2x0 C. and 0xc2x0 C. with xe2x88x9225xc2x0 C. to xe2x88x9220xc2x0 C. being preferred, before the addition of 1.2 to 1.7 equivalents of isobutyl chloroformate. The reaction is allowed to stir for 30 minutes to 3 hours to allow for the formation of the mixed anhydride. After the formation of the mixed anhydride is complete, sodium borohydride is added. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography, and recrystallization.
In Reaction Scheme C, step 5, the 5-oxo-3-(2-hydroxyethyl)-pyrrolidine of structure 17 is protected to give a 5-oxo-3-(xcfx89-protected-hydroxyethyl)pyrrolidine of structure 8 in which m is 2, r is 0, and q is 1 used in Reaction Scheme B for preparing compounds of structure 2. The selection and use of suitable protecting groups such as those described in Protecting Groups in Organic Synthesis by T. Greene is well known and appreciated in the art.
In Reaction Scheme C optional step 6, the 5-oxo-3-acetic acid ester pyrrolidine of structure 15 is reduced to give a 3-(xcfx89-hydroxyethyl)-pyrrolidine of structure 18 as taught in Reaction Scheme B, optional step 5.
In Reaction Scheme C, step 7, the 3-(xcfx89hydroxyethyl) pyrrolidine of structure 18 is aroylated with an appropriate aroyl halide, aryl anhydride, or aryl mixed anhydride, A1xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Ar2, to give an alcohol of structure 2. An appropriate aroyl halide, aryl anhydride, or aryl mixed anhydride, A1xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Ar2, is one in which A1 is an activated leaving group, such as chloro, bromo, or a group which forms an anhydride or mixed anhydride, n is as desired in the final product of formula (1), and Ar2 is as desired in formula (1) or gives rise after deprotection to Ar2 as desired in formula (1).
For example, the 3-(xcfx89-hydroxyethyl)pyrrolidine of structure 18 is contacted with 1 to 1.1 molar equivalents of an appropriate aroyl halide, aryl anhydride, or aryl mixed anhydride, A1xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Ar2. The reaction is carried out in a suitable solvent, such as tetrahydrofuran, dichloromethane, acetone, ethyl acetate, or diethyl ether. The reaction is carried out in the presence of a base, such as N-methylmorpholine, sodium carbonate, triethylamine, diisopropylethylamine, potassium carbonate or sodium bicarbonate. The reaction is generally carried out at temperatures of from xe2x88x9278xc2x0 C. to ambient temperature. Generally, the reactions require 1 to 24 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
Alternately, for example, the 3-(xcfx89-hydroxyethyl) pyrrolidine of structure 18 is contacted with 1 to 1.1 molar equivalents of an appropriate aroyl halide, arylanhydride, or aryl mixed anhydride, A1xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Ar2 under Schotten-Baumann conditions. The reaction is carried out in a suitable solvent mixture, such as acetone/water, tetrahydrofuran/water, or ethyl acetate/water. The reaction is carried out in the presence of a base, such as potassium carbonate, potassium bicarbonate, sodium bicarbonate, or sodium carbonate. The reaction is generally carried out at temperatures of from xe2x88x9220xc2x0 C. to 50xc2x0 C. Generally, the reactions require 15 minutes to 24 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Reaction Scheme C, optional step 8 the 5-oxo-3-acetic acid ester pyrrolidine of structure 15 is alkylated with an appropriate alkyl halide, X4xe2x80x94CH2xe2x80x94(CH2)nxe2x80x94Ar2, to give an 1-arylalkyl-5-oxo-3-acetic acid ester pyrrolidine of structure 19. An appropriate alkyl halide, X4xe2x80x94CH2xe2x80x94(CH2)nxe2x80x94Ar2, is one in which X4 is chloro, bromo, or iodo; n is as desired in the final product of formula (1), and Ar2 is as desired in formula (1) or gives rise after deprotection to Ar2 as desired in formula (1).
For example, the 5-oxo-3-acetic acid ester pyrrolidine of structure 15 is contacted with from 1.0 to 1.2 molar equivalents of an appropriate alkyl halide, X4xe2x80x94CH2xe2x80x94(CH2)nxe2x80x94Ar2. The reaction is carried out in a suitable solvent, such as tetrahydrofuran, dimethyl sulfoxide, acetonitrile, or dimethylformamide. The reaction is carried out in the presence of a base, such as sodium hydride, sodium bis(trimethylsilyl)amide, potassium t-butoxide. The reaction is generally carried out at temperatures of from 0xc2x0 C. to 50xc2x0 C. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Reaction Scheme C, step 9, the 1-arylalkyl-5-oxo-3-acetic acid ester pyrrolidine of structure 19 is hydrolyzed to give an 1-arylalkyl-5-oxo-3-acetic acid pyrrolidine of structure 20.
For example, the 1-arylalkyl-5-oxo-3-acetic acid ester pyrrolidine of structure 19 is contacted with a suitable hydrolyzing agent, such as sodium hydroxide, potassium hydroxide, or lithium hydroxide. The reaction is carried out in a suitable solvent such as water, tetrahydrofuran/water mixtures, methanol, methanol/water mixtures, or ethanol/water mixtures. The reaction is generally carried out at temperatures of from 0xc2x0C. to the refluxing temperature of the solvent. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Reaction Scheme C, step 10, the 1-arylalkyl-5-oxo-3-acetic acid pyrrolidine of structure 20 is reduced as taught in Reaction Scheme C, step 4, above, to give an alcohol of structure 2 in which r is 0, q is 1, m is 2, G1 is xe2x80x94C(O)xe2x80x94, and G2 and G3 are xe2x80x94CH2xe2x80x94.
Reaction Scheme D sets forth a synthetic procedure for preparing alcohols of structure 2 in which G1 is xe2x80x94CH2xe2x80x94 used as a starting material in Reaction Scheme A.1 and A.2. The reagents and starting materials used in Reaction Scheme D are readily available to one of ordinary skill in the art. In Reaction Scheme D, all substituents, unless otherwise indicated, are as previously defined. 
In Reaction Scheme D, step 1, an appropriate compound of structure 21 is alkylated with an appropriate alkylating agent to give an 1-arylalkyl-2-oxo compound of structure 22. An appropriate compound of structure 21 is one in which q is as desired in formula (1). An appropriate alkylating agent, Xxe2x80x94CH2xe2x80x94(CH2)nxe2x80x94Ar2, is as defined in Reaction Scheme B, optional step 4.
For example, an appropriate compound of structure 21 is contacted with from 1 to 5 molar equivalents of an appropriate alkylating agent, Xxe2x80x94CH2xe2x80x94(CH2)nAr2. The reaction is carried out in a suitable solvent, such as tetrahydrofuran. The reaction is carried out in the presence of a base, such as sodium hydride, potassium t-butoxide, potassium bis(trimethylsilyl)amide with potassium bis(trimethylsilyl)amide being preferred. The reaction is generally carried out at temperatures of from xe2x88x9278xc2x0 C. to the refluxing temperature of the solvent. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Reaction Scheme D, step 2, the 1-arylalkyl-2-oxo compound of structure 22 is arylmethylated with an appropriate arylmethylating agent to give a 1-arylalkyl-2-oxo-3-arylmethyl compound of structure 23. An appropriate arylmethylating agent, X5xe2x80x94CH2xe2x80x94Ar1, is one in which X5 is methanesulfonyl, chloro, bromo, or iodo and Ar1 is as desired in formula (1) or gives rise after deprotection to Ar1 as desired in formula (1). Examples of appropriate arylmethylating agents include, but are not limited to benzyl bromide, benzyl chloride, 3,4,5-trimethoxybenzyl methanesulfonate, 4-fluorobenzyl bromide, 4-fluorobenzyl chloride, 3,4-difluorobenzyl bromide, 3,4-difluorobenzyl chloride, 4-methoxybenzyl chloride, 3,4-dimethoxybenzyl bromide, 3,4-dimethoxybenzyl chloride, 3,4-dichlorobenzyl bromide, 3,4-dichlorobenzyl chloride, 3-chlorobenzyl bromide, 4-chlorobenzyl chloride, 2,4-difluorobenzyl bromide, 2,4-difluorobenzyl chloride, 2-(bromomethyl)thiophene, 2-(chloromethyl)pyridine, 3-(chloromethyl)pyridine, 4-(chloromethyl)pyridine, 1-(chloromethyl)naphthlene, 2-(chloromethyl)naphthlene, and the like.
For example, the 1-arylalkyl-2-oxo compound of structure 22 is contacted with from 1 to 5 molar equivalents of an appropriate arylmethylating agent. The reaction is carried out in a suitable solvent, such as tetrahydrofuran. The reaction is carried out in the presence of a base, such as sec-butyl lithium, n-butyl lithium, and lithium bis(trimethylsilyl)amide. The reaction is generally carried out at temperatures of from 0xc2x0 C. to xe2x88x9278xc2x0 C. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Reaction Scheme D, step 3, the 1-arylalkyl-2-oxo-3-arylmethyl compound of structure 23 is alkylated with an appropriate protected alcohol, Pg2Oxe2x80x94(CH2)mxe2x80x94L3, to give an 1-arylalkyl-2-oxo-3-arylmethyl-3-(-protected-hydroxyalkyl) compound of structure 24.
An appropriate protected alcohol, Pg2Oxe2x80x94(CH2))mxe2x80x94L3, is one in which m is as desired in the final product of formula (1) and the leaving group, L3, is one which can be displaced by an anion derived from an appropriate 1-arylalkyl-2-oxo-3-arylmethyl compound of structure 23. Suitable leaving groups, L3, include but are not limited to methanesulfonyl, chloro, bromo, and iodo. Suitable hydroxy protecting groups such as those described in Protecting Groups in Organic Synthesis by T. Greene are well known and appreciated in the art. In Reaction Scheme D, the use of t-butyldimethylsilyl is generally preferred.
For example, the 1-arylalkyl-2-oxo-3-arylmethyl compound of structure 23 is contacted with 1.0 to 1.2 molar equivalents of an appropriate protected alcohol, Pg2O-(CH2)mxe2x80x94L3. The reaction is carried out in the presence of an equimolar amount of a suitable base, such as sec-butyl lithium, n-butyl lithium, and lithium bis(trimethylsilyl)amide. The reaction is carried out in a solvent, such as tetrahydrofuran. The reaction is generally carried out at temperatures of from xe2x88x9278xc2x0 C. to 0xc2x0 C. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Reaction Scheme D, step 4, the 1-arylalkyl-2-oxo-3-arylmethyl-3-(-protected-hydroxyalkyl) compound of structure 24 is deprotected to give an alcohol of structure 2 in which r is 1 and G3 is xe2x80x94C(O)xe2x80x94. A deprotection reaction, such as the removal of hydroxy protecting groups utilizing suitable protecting groups such as those described in Protecting Groups in Organic Synthesis by T. Greene is well known and appreciated in the art.
In Reaction Scheme D, optional step 5, the 1-arylalkyl-2-oxo-3-arylmethyl-3-(-protected-hydroxyalkyl) compound of structure 24 is reduced to give an 1-arylalkyl-3-arylmethyl-3-(-protected-hydroxyalkyl) compound of structure 25.
This reaction is carried out as taught in reaction Scheme B, optional step 5 and may result in the removal of the protecting group Pg2. When the protection group Pg2 is removed the same or another protecting group Pg2 may be introduced or, alternately, the steps that follow may be carried out on the unprotected hydroxy compound.
In Reaction Scheme D, step 6, an appropriate 1-arylalkyl-3-arylmethyl-3-(-protected-hydroxyalkyl) compound of structure 25 is debenzylated to give a 3-arylmethyl-3-(xcfx89-protected-hydroxyalkyl) compound of structure 26. An appropriate 1-arylalkyl-3-arylmethyl-3-(xcfx89-protected-hydiroxyalkyl) compound of structure 25 is one in which n is 0 and Ar2 is phenyl or 4-methoxyphenyl; and m, q, and Ar1 are as desired in the final product of formula (l) or Ar1 gives rise after deprotection to an Ar1 as desired in the final product of formula (1).
For example, and an appropriate 1-arylalkyl-3-arylmethyl-3-(xcfx89-protected-hydroxyalkyl) compound of structure 25 is hydrogenated. The reaction is carried out in a suitable solvent, such as ethanol, methanol, or water. The reaction is carried out in the presence of a suitable catalyst, such as 20% palladium hydroxide-on-carbon. The reaction is carried out at pressures of from atmospheric pressure to about 100 psi. When the reaction is carried out at a pressure greater than atmospheric pressure, the reaction is carried out in a suitable pressure apparatus, such as a Parr apparatus or an autoclave. The reaction is generally carried out at temperatures of from 50xc2x0 C. to 0xc2x0 C. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as filtration, evaporation, trituration, chromatography, and recrystallization.
In Reaction Scheme D, step 7, the 3-arylmethyl-3-(xcfx89-protected-hydroxyalkyl) compound of structure 26 is aroylated as taught in Reaction Scheme B, optional step 7 to give an 1-aroyl-3-arylmethyl-3-(xcfx89-protected-hydroxyalkyl) compound of structure 27.
In Reaction Scheme D, step 8, the 1-aroyl-3-arylmethyl-3-(xcfx89-protected-hydroxyalkyl) compound of structure 27 is deprotected, if required, to give an alcohol of structure 2 in which r is 1, G3 is xe2x80x94CH2xe2x80x94, and G2 is xe2x80x94C(O)xe2x80x94. A deprotection reaction, such as the removal of hydroxy protecting groups utilizing suitable protecting groups such as those described in Protecting Groups in Organic Synthesis by T. Greene is well known and appreciated in the art.
Reaction Scheme E sets forth the preparation of alcohols of structure 2 in which r is 0 and G1 is xe2x80x94CH2xe2x80x94 used as a starting material in Reaction Scheme A.1 and A.2. The reagents and starting materials are readily available to one of ordinary skill in the art. In Reaction Scheme E, all substituents, unless otherwise indicated, are as previously defined. 
In Reaction Scheme E, step 1, an appropriate methyl arylacetate of structure 28 is alkylated with an appropriate xcfx89-cyano alkylating agent of structure 29 to give a cyano ester of structure 30.
An appropriate methyl arylacetate of structure 28 is one in which Ar1 is as desired in formula (1) or gives rise after deprotection to Ar1 as desired in formula (1). An appropriate xcfx89-cyano alkylating agent of structure 29 is one in which q is as desired in formula (1) and L4 is chloro or bromo. Examples of appropriate xcfx89-cyano alkylating agents of structure 29 include xcex1-chloroacetonitrile, xcex1-bromoacetonitrile, acrylonitrile, xcex2-chloropropionitrile, and xcex2-bromopropionitrile.
For example, an appropriate methyl arylacetate of structure 28 is contacted with from 0.8 to 1.2 molar equivalents of an appropriate xcfx89-cyano alkylating agent of structure 29. The reaction is carried out in a suitable solvent, such as tetrahydrofuran. The reaction is carried out in the presence of a base, such as sodium hydride, lithium bis(trimethylsilyl)amide, or potassium bis(trimethylsilyl)amide. The reaction is generally carried out at temperatures of from 0xc2x0 C. to xe2x88x9278xc2x0 C. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
In Reaction Scheme E, step 2, the cyano ester of structure 30 is reduced and cyclized to give a 2-oxo-3-aryl compound of structure 31 as taught in Reaction Scheme B, step 3.
In Reaction Scheme E, step 3, the 2-oxo-3-aryl compound of structure 31 is alkylated with an appropriate alkylating agent as taught in Reaction Scheme D, step 1, to give an 1-arylalkyl-2-oxo-3-aryl compound of structure 32.
In Reaction Scheme E, step 4, the 1-arylalkyl-2-oxo-3-aryl compound of structure 32 is alkylated with an appropriate protected alcohol, Pg2Oxe2x80x94(CH2)mxe2x80x94L3, as taught in Reaction Scheme D, step 3, to give a 3-(xcfx89-protected-hydroxyalkyl)-1-arylalkyl-2-oxo-3-aryl compound of structure 33.
In Reaction Scheme E, step 5, the 3-(xcfx89-protected-hydroxyalkyl)-1-arylalkyl-2-oxo-3-aryl compound of structure 33 is deprotected to give an alcohol of structure 2 in which r is 0 and G3 is xe2x80x94C(O)xe2x80x94. A deprotection reaction, such as the removal of hydroxy protecting groups utilizing suitable protecting groups such as those described in Protecting Groups in Organic Synthesis by T. Greene is well known and appreciated in the art.
In Reaction Scheme E, optional step 6, the 3-(xcfx89-protected-hydroxyalkyl)-1-arylalkyl-2-oxo-3-aryl compound of structure 33 is reduced to give a 3-(xcfx89-protected-hydroxyalkyl)-1-arylalkyl-3-aryl compound of structure 34.
This reaction is carried out as taught in reaction Scheme 3, optional step 5 and may result in the removal of the protecting group Pg2. When the protection group Pg2 is removed the same or another protecting group Pg2 may be introduced or, alternately, the steps that follow may be carried out on the unprotected hydroxy compound.
In Reaction Scheme E, step 7, an appropriate 3-(xcfx89-protected-hydroxyalkyl)-1-arylalkyl-3-aryl compound of structure 34 is debenzylated as taught in Reaction Scheme D, step 6, to give a 3-(xcfx89-protected-hydroxyalkyl)-3-aryl compound of structure 35. An appropriate 3-(xcfx89-protected-hydroxyalkyl)-1-arylalkyl-3-aryl compound of structure 34 is one in which n is 0 and Ar2 is phenyl or 4-methoxyphenyl; and m, q, and Ar1 are as desired in the final product of formula (1) or Ar1 gives rise after deprotection to an Ar1 as desired in the final product of formula (1).
In Reaction Scheme E, step 8, a 3-(xcfx89-protected-hydroxyalkyl)-3-aryl compound of structure 35 is aroylated as taught in Reaction Scheme B, optional step 7 to give an 1-aroyl-3-(xcfx89-protected-hydroxyalkyl)-3-aryl compound of structure 36.
In Reaction Scheme E, step 9, the 1-aroyl-3-(xcfx89-protected-hydroxyalkyl)-3-aryl compound of structure 36 is deprotected, if required, to give an alcohol of structure 2 in which r is 0, G3 is xe2x80x94CH2xe2x80x94, and G2 is xe2x80x94C(O)xe2x80x94. A deprotection reaction, such as the removal of hydroxy protecting groups utilizing suitable protecting groups such as those described in Protecting Groups in Organic Synthesis by T. Greene is well known and appreciated in the art.
The following examples and preparations present typical syntheses of the compounds of formula (1). These examples are understood to be illustrative only and are not intended to limit the scope of the invention in any way.
4-(1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
According to the method of R. Iemura et al., J. Med. Chem., 29 1178-1183 (1986), combine 1-chloro-2-nitrobenzene (69.0 g, 440 mmol) and 2-aminoethyl ethyl ether (102.5 g, 1.15 mol) and heat to reflux. After 18 hours, cool and dilute the reaction mixture with ethyl acetate (400 mL). Extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane to give N-(2-ethoxyethyl)-2-nitroaniline.
Combine N-(2-ethoxyethyl)-2-nitroaniline (85.4 g, 406 mmol) and ethanol (300 mL). Add a solution of sodium hydroxide (6 g) in water (60 mL). Heat to reflux. Remove the heating and add portionwise zinc metal (106 g, 1.62 mol) at a rate such that the reaction is maintained at reflux. After the addition of zinc metal is complete stir for 30 minutes. Filter the reaction mixture and rinse with water. Extract the filtrate three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give 1-(2-ethoxyethyl)-1,2-phenylenediamine.
Combine 1-(2-ethoxyethyl)-1,2-phenylenediamine (55.4 g, 307 mmol) and urea (37.5 g, 624 mmol). Heat at 150xc2x0 C. After 5 hour, cool to ambient temperature and stir. After 18 hours, partition the reaction mixture between ethyl acetate and water. Separate the layers and extract the aqueous layer three times with ethyl acetate. Combine the organic layers and extract with aqueous 1 M hydrochloric acid solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane to give the 2-hydroxy-1-(2-ethoxyethyl)-1H-benzimidazole.
Combine 2-hydroxy-1-(2-ethoxyethyl)-1H-benzimidazole (36.4 g, 177 mmol) and phosphorous oxychloride (72 mL) and reflux. After 30 minutes, cool to ambient temperature and pour the reaction mixture onto crushed ice. Adjust the pH to about 9 using aqueous 50% sodium hydroxide solution. Extract three times with ethyl acetate. Combine the organic layers and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole.
Combine 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole (12.2 g, 54.2 mmol) and [1,4]diazepane (11.34 g, 113 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (9 mL), and pyridine (90 mL). Heat to reflux. After 18 hours, cool to ambient temperature and evaporate in vacuo to give a residue. Partition the residue between aqueous 1 M sodium hydroxide solution and ethyl acetate. Separate the layers and extract the aqueous layer two times with ethyl acetate. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 30% methanol/ethyl acetate and then 2% concentrated aqueous ammonia/methanol to give the title compound: Rf=0.26 (silica gel, 2% concentrated aqueous ammonia/methanol).
Alternately, combine 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole (15.56 g, 69.3 mmol) and [1,4]diazepane (13.89 g, 138.7 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (12.34 mL, 83.1 minol), and pyridine (200 mL). Heat to reflux. After 18 hours, cool to ambient temperature and evaporate in vacuo to give a residue. Partition the residue between aqueous 1 M sodium hydroxide solution and dichloromethane. Separate the layers and extract the aqueous layer two times with dichloromethane. Combine the organic layers, extract with aqueous 1 M sodium hydroxide solution, water, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 2% concentrated aqueous ammonia/methanol to give the title compound: Rf=0.26 (silica gel, 2% concentrated aqueous ammonia/methanol).
4-(1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane
Combine 2-chloro-1H-benzimidazole (21.1.4 g, 138.4 mmol) and dimethylformamide (200 mL). Add portionwise, sodium hydride (24.0 g, 60% in oil, 153.3 mmol). After 15 minutes, add 2-chloroethyl ethyl ether (21.9 g, 201,5 mmol). Heat to 60xc2x0 C. After 18 hours, cool the reaction mixture and dilute with ethyl acetate. Extract with a saturated aqueous sodium bicarbonate solution, water, and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 10% ethyl acetate/hexane and then 30% ethyl acetate hexane to give the 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole: Rf=0.74 (silica gel, 7/3 ethyl acetate/hexane).
Combine 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole (22.3 g, 99.4 mmoL), 1-methyl[1,4]diazepane (19 mL, 152.8 mmol), and triethylamine (75 mL). Heat to 70xc2x0 C. After 18 hours, add 1-methyl[1,4]diazepane (10 mL) and continue to heat at reflux. After 96 hours, cool to ambient temperature and partition the reaction mixture between water and ethyl acetate. Separate the layers and extract the organic layer with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 50% ethyl acetate/hexane and then 10% methanol/dichloromethane to give 1-methyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.52 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia, 90/10/0.1).
Combine 1-methyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.79 g, 5.9 mmol) and ethyl chloroformate (0.75 mL, 7.8 mmol) in toluene (20 mL). Heat to 80xc2x0 C. After 2 hours, cool the reaction mixture and dilute with ethyl acetate. Extract with a saturated aqueous sodium bicarbonate solution, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-ethoxycarbonyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.87 (silica gel, dichloromethane/methanol, 90/10).
Combine 1-ethoxycarbonyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (17.2 g, 47.6 mmol), hydrazine hydrate (40 mL), and potassium hydroxide (40.7 g, 725 mmol) in ethylene glycol (150 mL). Heat to reflux. After 5 hours, cool the reaction mixture and dilute with water (500 mL). Extract three times with dichloromethane. Combine the dichloromethane layers and extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf=0.25 (silica gel, dichloromethane/methanol, 90/10).
4-(1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane Hydriodic Acid Salt
Combine 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.30 g), 48% hydriodic acid (10 mL), ethanol (10 mL), and diethyl ether (80 mL) and stir. After 30 minutes add diethyl ether, (800 mL) and continue to stir to give a solid. Collect the solid by filtration and dry in vacuo to give the title compound: mp; 156-163xc2x0 C.
Alternately, combine 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (18.42 g, 63.9 mmol), 57% hydriodic acid (8.30 mL), ethanol (80 mL) and stir. After 2.5 hours, cool to give a solid. Collect the solid by filtration, rinse with diethyl ether, and dry in vacuo to give the title compound.